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Original Research |
1 Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe Universität,
Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
2 Department of Radiology, Saarland University Hospital, Homburg, Germany.
3 Department of Pathology, Saarland University Hospital, Homburg, Germany.
4 Faculty of Medicine, Internal Medicine–Biomathematics, Saarland
University, Homburg, Germany.
Received December 18, 2007;
accepted after revision June 28, 2008.
Address correspondence to J. Bojunga
(Joerg.Bojunga{at}kgu.de).
Abstract
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SUBJECTS AND METHODS. Thirty-five consecutively registered patients with newly detected adrenal masses underwent hormonal evaluation and duplex and Doppler sonography followed by contrast-enhanced sonography and CT or MRI. The dynamics of contrast enhancement were analyzed with time–intensity curves. CT and MRI were used as the reference methods for the diagnosis of adenoma and myelolipoma. Metastasis was diagnosed with fine-needle biopsy, and all other adrenal masses were diagnosed at adrenalectomy. Fisher's exact test was used to evaluate the criteria for diagnosis of malignant adrenal masses.
RESULTS. Size greater than 4 cm and hypervascularization were found significantly more often in malignant than in benign lesions (71% vs 21% for size; 57% vs 7% for hypervascularization). At contrast-enhanced sonography, early arterial or arterial contrast enhancement and rapid washout were seen in all patients with primary or secondary malignant lesions of the adrenal gland and in only 22% of patients with benign adrenal masses (p < 0.05). All primary malignant lesions were confirmed at histologic examination. In 32 of 35 patients (91%), findings at CT or MRI were congruent with those at contrast-enhanced sonography in regard to characterization of adenoma versus nonadenomatous lesion (p < 0.001). In two of the 35 cases, however, all imaging methods favored the diagnosis of nonadenomatous lesion, but the histologic result after adrenalectomy was adrenal adenoma. The sensitivity and specificity of contrast-enhanced sonography in the diagnosis of malignant adrenal mass were 100% and 82%.
CONCLUSION. Contrast-enhanced sonography can be used to differentiate adenomas and nonadenomatous lesions with a sensitivity comparable with that of CT and MRI and may be a cost-effective method for preselection of patients with adrenal masses.
Keywords: adenoma • adrenal gland • contrast-enhanced sonography • incidentaloma • nonadenomatous • sonography
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In only one pilot study [6] to our knowledge has contrast-enhanced Doppler sonography of adrenal masses with the contrast agent SH U 508A (Levovist, Bayer Schering Pharma) been evaluated. The investigators found improved visualization of the vascularization of adrenal masses during power Doppler sonography. However, differentiation of benign and malignant adrenal masses was not possible in that study. To our knowledge, no study has been conducted to examine adrenal glands and adrenal masses with a contrast agent consisting of a suspension of phospholipid-stabilized microbubbles filled with sulfur hexafluoride (SonoVue, Bracco), which has the advantage that contrast enhancement and washout can be followed for up to 5 minutes.
With advances in diagnostic imaging, differentiation of malignant and benign adrenal masses has improved substantially. CT and MRI can be used to characterize benign adrenal masses in most patients with adrenal masses. Whereas in the era before highly specialized CT and MRI 40–57% of patients with adrenal adenomas underwent biopsy for diagnosis, only 12% of these patients undergo biopsy at present [7]. Studies [8–12] have shown that benign and malignant adrenal masses can be differentiated at CT with a sensitivity of 85–100% and a specificity of 100–95%. If an adrenal mass remains indeterminate after CT, MRI or adrenal biopsy is performed [13–15].
CT and MRI, however, are expensive examinations compared with sonography. CT is associated with substantial radiation exposure, and CT and MRI are commonly performed in addition to screening sonography. Furthermore, adenomas are much more common than nonadenomatous lesions, and many CT and MRI examinations are performed only to rule out malignancy. Therefore, preselection of patients with suspicious adrenal masses at screening sonography would be favorable. If this screening can be performed with high sensitivity, the number of patients who need additional diagnostic imaging with CT or MRI would be markedly reduced, and malignant lesions would not be missed. We conducted a proof-of-principle study to evaluate contrast-enhanced sonography in the characterization of adrenal masses.
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All patients underwent sonography of the adrenal mass that included duplex and Doppler sonography followed by contrast-enhanced sonography. In addition, all patients underwent CT, MRI, or both. Patients without clear signs of a benign adrenal mass on MRI or CT underwent fine-needle aspiration biopsy or adrenalectomy and histologic evaluation of the specimen. The study was performed in accordance with the ethical guidelines of the Declaration of Helsinki. Informed consent in compliance with legislation was obtained from each patient.
Sonographic Examination
All patients were examined in the supine position with B-mode Doppler
sonography with a 3.5-MHz transducer (EUB-8500, Hitachi). The sonographic
examinations were performed by two experienced examiners blinded to the
results of MRI and CT. All patients had fasted overnight. The adrenal mass was
examined for size, echogenicity, echotexture, margins, and perfusion pattern.
After B-mode sonography, conventional power Doppler imaging was performed.
Vascularization of the adrenal mass was classified as hypovascular,
isovascular, or hypervascular in comparison with the vascularization of the
liver or spleen. The presence of specific vascular patterns, such as afferent
blood vessels and irregular tumor vessels was recorded.
Contrast-enhanced dynamic sonography was performed with contrast-specific continuous-mode software with a 3.5-MHz transducer (EUB-8500) and a low mechanical index (0.11). Aqueous suspension of phospholipid-stabilized microbubbles filled with sulfur hexafluoride (SonoVue) was used as the sonographic contrast agent. The contrast agent was injected IV in a 4.8-mL bolus through a 20-gauge cannula into an antecubital vein and was followed by a 10-mL saline flush. The adrenal mass was scanned for 5 minutes with the liver (right adrenal mass) or spleen (left adrenal mass) as an in vivo reference. The first contrast enhancement was observed and categorized in the early arterial phase (< 20 seconds after injection), arterial phase (20–40 seconds after injection), and parenchymal (late) phase (> 40 seconds–5 minutes after injection). Specific vascularization patterns such as central, peripheral, and chaotic contrast enhancement were assessed.
The video clip was digitally recorded, and a region of interest was placed in the adrenal mass and in the reference organ (spleen or liver) and analyzed over time with time–intensity curves. Contrast enhancement was compared with preinjection values and expressed in percentage of baseline value. The perfusion patterns were compared with the CT and MRI diagnoses and judged congruent or noncongruent with CT or MRI findings for differentiation of adenoma and nonadenomatous lesions.
CT and MRI
If the incidental diagnosis of adrenal mass was made at CT performed for
other purposes, such as abdominal pain, staging of primary malignant tumor,
and hormonal dysfunction, the CT scans were reviewed for quality criteria by a
radiologist with 20 years of experience. Only a triple-phase helical CT
examination with delayed contrast enhancement (iomeprol 400 mg I/mL, Iomeron
400, Bracco) was accepted for analysis. Percentage of washout was calculated
with the following formula: (1 – delayed enhanced attenuation value /
initial enhanced attenuation value) x 100
[16]. If clear criteria for a
benign adrenal mass were present (unenhanced attenuation 
10 HU and CT
contrast washout 
50% 10 minutes after contrast administration)
[16,
17], no additional MRI was
performed.
If the primary diagnosis of adrenal mass was found during a sonographic examination, low-image-quality CT, or CT without clear benign criteria, MRI was performed at our clinic. MRI was performed on a 1.5-T unit (Vision, Siemens Medical Solutions). The MRI examinations included unenhanced T1-weighted and T2-weighted sequences, chemical shift imaging (in- and out-of-phase imaging), and dynamic T1-weighted contrast-enhanced imaging (gadobenate dimeglumine, MultiHance, Bracco).
MRI was performed with T2-weighted turbo spin-echo sequences (TR/TE, 4,000/108; flip angle, 150°; echo-train length, 29), a T2-weighted RARE sequence (HASTE, Siemens Medical Solutions) (infinite/74; flip angle, 180°), and T1-weighted gradient-recalled echo in-phase (160/4.7; flip angle, 70°) and out-of phase (160/2.6; flip angle, 70°) images. For dynamic contrast-enhanced imaging, a T1-weighted FLASH 2D sequence (174.9/4.1; flip angle, 80°) was used during the arterial (20–25 seconds after injection), portal venous (50–60 seconds after injection), and equilibrium (> 5 minutes after injection) phases of contrast enhancement. The field of view for all sequences was 350–450 mm2, and the matrix size was 107–186 x 256. All sequences were performed with a breath-hold. The contrast agent was administered with a power injector at a constant injection rate of 2.5 mL/s. The dose of gadopentetate dimeglumine (Magnevist, Schering) was 0.1 mmol/kg body weight, corresponding to 0.2 mL/kg body weight of a 0.5 mol/L formulation injected in a volume based on body weight and followed by a 20-mL saline flush.
Criteria for the diagnosis of adenoma on MRI were homogeneous signal intensity on unenhanced T2-weighted and T1-weighted images, homogeneous enhancement on dynamic images after contrast injection (0.1 mmol/kg body weight of gadopentetate dimeglumine), and loss of signal intensity of the lesion on out-of phase images (evaluated by visual assessment of signal intensity loss on opposed-phase images compared with inphase images) [18]. As an internal standard, the signal intensity of the adrenal mass was compared with the signal intensity of the spleen.
Hormonal Evaluation
In addition to routine laboratory testing, a specific evaluation to detect
the hormonal activity of an adrenal mass was performed on all patients after
overnight fasting. The hormonal evaluation included base levels of
corticotropin, cortisol, dehydroepiandrosterone sulfate, aldosterone, renin
activity, plasma-free normetanephrine, plasma-free metanephrine, and
chromogranin A. In addition, an overnight dexamethasone suppression test with
2 mg of dexamethasone was performed to rule out Cushing's syndrome. A plasma
aldosterone concentration to plasma renin activity ratio of less than 20
together with an aldosterone concentration within the normal range and a
cortisol concentration of less than 3 µg/dL after an overnight suppression
test were considered normal. The laboratory results were judged by an
endocrinologist with 14 years of experience.
Final Reference Diagnosis
The reference standard was determined by an experienced radiologist and an
experienced endocrinologist working together. The final reference diagnosis
was defined by combining all available information from imaging (CT and MRI)
and additional information from the hormonal evaluation and histologic
examination. Postsurgical histologic verification of adrenal masses after
adrenalectomy was available in 10 cases. Metastatic lesions (n = 3)
were diagnosed with fine-needle biopsy. In the other 22 cases, the diagnosis
was confirmed with CT (n = 10) or MRI (n = 12).
Statistical Analysis
Statistical analysis was performed with SPSS software (version 12.0, SPSS).
Clinical and laboratory characteristics of patients were expressed as mean
± SD, median, and range. Fisher's exact test was used to evaluate the
criteria for diagnosis of malignant adrenal masses. A value of p <
0.05 was judged to be statistically significant.
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Contrast-Enhanced Sonography
Four patterns of sonographic contrast enhancement were found (Figs.
1A,
1B,
1C, and
1D). Nine adrenal masses
exhibited early arterial contrast enhancement (< 20 seconds) with an
intensity peak between 11 and 43 seconds followed by rapid washout (pattern
1). Three adrenal masses exhibited arterial contrast enhancement beginning in
the arterial phase (21–40 seconds) with an intensity peak after
43–86 seconds (pattern 2). Fourteen adrenal masses exhibited late and
little contrast enhancement in the late phase (> 40 seconds) with an
intensity peak after 60–110 seconds (pattern 3). Nine adrenal masses
exhibited no recordable contrast enhancement (pattern 4).
Contrast-Enhanced Sonographic Findings in Comparison with CT, MRI, and Histologic Findings
All nine adrenal masses with early arterial peak enhancement with rapid
washout on sonograms (pattern 1) exhibited the criteria for nonadenomatous
lesions on CT or MRI. Six of these nine adrenal masses exhibited criteria of
malignancy on CT and MRI, and three were suspected of being pheochromocytoma
according to MRI findings. Fine-needle biopsy revealed metastasis of lung
cancer in two of the nine lesions, and the patients with the other seven
adrenal masses were transferred to surgery. Examination of the histologic
specimens confirmed the presence of malignancy in four cases (two
nonfunctional adrenocortical carcinomas, one cortisol-producing adrenocortical
carcinoma, and one T-cell lymphoma). The other three lesions were benign (one
pheochromocytoma, one adrenal adenoma, and one partially thrombosed cavernous
hemangioma). Among the three lesions suspected of being pheochromocytoma at
MRI, the histologic finding was pheochromocytoma in only one case; the other
two lesions were carcinoma and adenoma. The adenoma exhibited central
hemorrhage and calcification. All patients tolerated surgery without
complications.
In addition to the nine lesions with sonographic pattern 1, three other adrenal masses were resected. Two of these lesions (22 x 15 mm and 30 x 26 mm) had a suspicious appearance on CT or MRI, and one lesion was large (55 x 50 mm) and caused local symptoms. The former two adrenal masses exhibited sonographic contrast enhancement patterns 3 and 2, respectively, and the latter, pattern 3. The former two masses were histologically adrenal adenoma, and the latter had MRI evidence of myelolipoma.
Among the 10 cases managed surgically, the correct diagnosis concerning the histopathologic entity was made with CT and MRI in three cases. No differentiation between primary and secondary malignant tumors of the adrenal gland was possible at contrast-enhanced sonography. Eight of the 10 resected lesions were found to be nonadenomatous at sonography with the use of contrast enhancement patterns 1 and 2 for the diagnosis of nonadenomatous lesions.
Among the nine adrenal masses with no contrast enhancement on sonography (pattern 4), all but one had CT or MRI evidence of adrenal adenoma, and one was a metastatic lesion after successful chemotherapy and in accordance with the sonographic findings did not exhibit perfusion at MRI. This lesion was therefore judged to be nonadenomatous and nonmalignant.
Among the 14 adrenal masses with slow and late contrast enhancement at sonography (pattern 3), 11 were diagnosed as adrenal adenomas on the basis of CT or MRI findings. One mass was misdiagnosed as metastasis at CT, but the histologic finding was adenoma (Table 1). One mass was diagnosed as adrenal hyperplasia at MRI, and one as myelolipoma at MRI and histologic examination. All three adrenal masses with arterial contrast enhancement on sonography (pattern 2) beginning in the arterial phase had the CT or MRI criteria of a nonadenomatous lesion (one myelolipoma, one metastatic lesion, and one lesion deemed metastatic at MRI but found to be adenoma at histologic examination). With patterns 3 and 4 as the criteria for benign adrenal mass and patterns 1 and 2 as the criteria for malignant lesion, the diagnosis of malignant lesion was made with contrast-enhanced sonography with a sensitivity of 100% (95% CI, 60–100%), specificity of 82% (64–93%), positive predictive value of 58% (32–81%), and negative predictive value of 100% (83–100%).
In 91.4% (32 of 35) of examined patients, the findings at CT or MRI and contrast-enhanced sonography were congruent concerning the characterization of adenoma versus nonadenomatous lesion. In two of these cases, however, findings with all imaging methods suggested a nonadenomatous lesion, but histologic examination after adrenalectomy revealed adrenal adenoma. One of the cases of divergent findings at CT or MRI and contrast-enhanced sonography was metastasis after chemotherapy without remaining vascularization. Perfusion was seen neither on MRI nor on contrast-enhanced sonography, but the lesion could not be differentiated from adenoma at sonography. In the two other cases of divergent findings, the correct diagnosis was made at CT or MRI in one case (angiomyelolipoma) and with contrast-enhanced sonography in the other case (adenoma).
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Another patient had clinical and laboratory signs of pheochromocytoma with a plasma metanephrine concentration of 2,531 pg/mL (normal range < 90 pg/mL) and plasma normetanephrine concentration of 466 pg/mL (normal range < 200 pg/mL). The MRI findings were congruent with the diagnosis of pheochromocytoma. Contrast-enhanced sonography showed pattern 1 vascularization. Histologic examination revealed benign pheochromocytoma.
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The incidence of incidentaloma found in autopsy and CT studies is 4–6% [19–21]. Noninvasive differentiation of benign and malignant adrenal masses is essential for reducing the number of expensive and invasive imaging studies performed. A high sensitivity for the diagnosis of malignancy is needed to ensure that a primary or secondary malignant lesion of the adrenal gland is not missed. Conversely, specificity for the diagnosis of malignancy is less critical, because the worst consequence of a false-positive diagnosis is that an additional or invasive examination is necessary to establish the correct diagnosis. In our proof-of-principle study, contrast-enhanced sonography fulfilled these criteria with a sensitivity of 100% and a specificity of 82% in the diagnosis of malignant lesions of the adrenal gland.
As reported in previous studies [3] and found in our study, the average size of benign adrenal masses is smaller than that of malignant adrenal masses (30 x 39 mm vs 60 x 77 mm). In a study involving 887 patients with adrenal incidentaloma, a diameter greater than 4 cm was found to have 90% sensitivity and 24% specificity in the detection of adrenocortical carcinoma [22]. In our study, 11 adrenal masses were larger than 4 cm in diameter, and three of these lesions were adrenocortical carcinoma, for a sensitivity of 100% (95% CI, 38–100%) and specificity of 75% (58–87%). The prevalence of adrenocortical carcinoma was 8.6%, higher than the 4.7% reported in the literature [21]. A size greater than 4 cm was found to have a sensitivity of 71% and a specificity of 79% in the detection of malignant adrenal masses. Therefore, in accordance with previously published data [22, 23], no sufficient conclusion concerning the benignity of the adrenal mass could be drawn solely from the size of the mass.
According to present recommendations [17], all patients received a hormonal evaluation (after the history interview and physical examination) as the first diagnostic procedure. In this study, two adrenal masses (6%) were functional (Cushing's syndrome and pheochromocytoma). Both patients were referred for surgery, and the diagnosis was confirmed. According to the literature [23], approximately 85% of adrenal incidentalomas are nonfunctional, and 15% are functional. The slightly lower number of functional adenomas in our study might have been due to the small number of patients examined in this pilot study. Another explanation may be that an increasing number of incidentalomas are detected as the result of improvements in sonographic systems and the inclusion of adrenal gland examinations during screening sonography.
According to current recommendations [17], all patients with negative results at hormonal testing underwent high-quality CT or underwent MRI at our clinic to differentiate benign and suspicious lesions that necessitated further evaluation. Contrast-enhanced CT and gadolinium-enhanced MRI have excellent sensitivity, specificity, and positive predictive value in the diagnosis of benign adrenal mass and are currently accepted as reference methods in the evaluation of nonfunctional adrenal masses smaller than 4 cm in diameter [16, 17, 24–29]. Therefore, CT or MRI was used as the reference standard when signs of adenoma were overt, as they were in the 22 patients with nonfunctional adrenal masses. These patients were not referred for surgery. Imaging (after 6, 12, and 24 months) and laboratory (annually for 4 years) follow-up was suggested [17, 24]. Three patients with metastasis of primary lung cancer did not undergo surgery because of the palliative treatment concept. The diagnosis was confirmed with fine-needle biopsy.
In accordance with present recommendations [17], all nine patients with suspicious findings at imaging were referred for surgery. Malignancy was found in four patients, and pheochromocytoma and myelolipoma were confirmed in two patients. The misdiagnosis of adenoma for a nonadenomatous lesion at CT or MRI can be explained by the presence of hemorrhage and calcification in the large adenomas.
An algorithm for the evaluation of adrenal incidentaloma starts with a history interview, physical examination, and hormonal testing [17]. The next step, if the findings are normal, is imaging for phenotype. At this point, in light of the results of our study, contrast-enhanced sonography can be used as the first and most cost-effective imaging method for differentiating benign and suspicious appearances. Because the sensitivity for the diagnosis of a malignant lesion in this study was 100%, no malignant lesions were missed. Because adenomas are common and malignancy of incidentally diagnosed adrenal masses is rare, contrast-enhanced sonography may be a useful tool for excluding most adenomas and selecting patients who need additional diagnostic evaluation.
Because the specificity of MRI and CT is higher than that of contrast-enhanced sonography, the next step for all suspicious lesions should be a second imaging study (CT or MRI). However, the number of CT and MRI examinations needed can be markedly reduced if preselection is performed with contrast-enhanced sonography. Therefore, considerable cost reduction can be attained with the expanded algorithm. On the basis of the results of this proof-of-principle study, more extensive studies of contrast-enhanced sonography for the characterization of adrenal masses are needed for confirmation of our preliminary data.
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